title: Promotion of melanoma cell invasion and tumor metastasis by microcystin-LR via phosphatidylinositol 3-kinase/AKT pathway.
abstract: Recently, we have indicated that microcystin-LR, a cyanobacterial toxin produced in eutrophic lakes or reservoirs, can increase invasive ability of melanoma MDA-MB-435 cells; however, the stimulatory effect needs identification by in vivo experiment and the related molecular mechanism is poorly understood. In this study, in vitro and in vivo experiments were conducted to investigate the effect of microcystin-LR on invasion and metastasis of human melanoma cells, and the underlying molecular mechanism was also explored. MDA-MB-435 xenograft model assay showed that oral administration of nude mice with microcystin-LR at 0.001-0.1 mg/kg/d posed no significant effect on tumor weight. Histological examination demonstrated that microcystin-LR could promote lung metastasis, which is confirmed by Matrigel chamber assay suggesting that microcystin-LR treatment at 25 nM can increase the invasiveness of MDA-MB-435 cells. In vitro and in vivo experiments consistently showed that microcystin-LR exposure increased mRNA and protein levels of matrix metalloproteinases (MMP-2/-9) by activating phosphatidylinositol 3-kinase (PI3-K)/AKT. Additionally, microcystin-LR treatment at low doses (≤25 nM) decreased lipid phosphatase PTEN expression, and the microcystin-induced invasiveness enhancement and MMP-2/-9 overexpression were reversed by the PI3-K/AKT chemical inhibitor LY294002 and AKT siRNA, indicating that microcystin-LR promotes invasion and metastasis of MDA-MB-435 cells via the PI3-K/AKT pathway.
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University , Nanjing 210029, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Xu
authors.forename: Xu-Xiang
authors.initials: XX
authors.lastname: Zhang
authors.forename: Chen
authors.initials: C
authors.lastname: Miao
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Fu
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Li
authors.forename: Gen
authors.initials: G
authors.lastname: Zhang
authors.forename: Maqing
authors.initials: M
authors.lastname: Zheng
authors.forename: Yuefang
authors.initials: Y
authors.lastname: Liu
authors.forename: Liuyan
authors.initials: L
authors.lastname: Yang
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008387:Marine Toxins; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D052998:Microcystins / Q000633:toxicity*; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
chemical_list: D008387:Marine Toxins; D052998:Microcystins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C057862:cyanoginosin LR